We have been able to weave together a unique explanation for the severe oxidative damage that exacerbates combined burn/smoke-induced cardiopulmonary injury we originally reported in 1992. We hypothesize that inducible nitric oxide synthase (iNOS) plays a major role in this injury. The injury damages DNA, activating poly (ADP-ribose) polymerase (PARP) that activates nuclear factor-KappaB (NF-KappaB) and up-regulates iNOS. Lung NO overproduction results in loss of hypoxic pulmonary vasoconstriction. NO can also form reactive nitrogen species (RNS) that damage the alveolar epithelium and capillary endothelium resulting in pulmonary edema. Injury can be ameliorated by increasing arginine availability (both supply and extraction rates) that prevents the conversion of iNOS from a protective to injurious state. We further hypothesize that the liver is damaged by reactive oxygen species (ROS) and RNS derived both from the initial injury and resulting inflammatory responses. ROS and RNS consume antioxidants, especially circulating and tissue vitamin E. Lower vitamin E levels increase the body's susceptibility to oxidative damage. We test these hypotheses with the following specific aims in ovine and murine models of bum and smoke inhalation injury: Aim 1. Establish the role of PARP as the initiator of the cardiopulmonary injury after combined bum and smoke exposure by defining the time course of PARP, NF-KappaB and iNOS expression, NOx, and RNS formation and tissue oxidation. Aim 2. Establish the role of excess arginine and/or vitamin E availability in protection from injury by determining changes in lung lymph flow and oxygenation induced by bum and smoke injury. Aim 3. Establish the protective and damaging roles of iNOS in the response to injury by using a) specific inhibitor of iNOS, b) excess vitamin E and c) iNOS null mice. An understanding of the oxidative damage may greatly simplify and improve treatment. Adequate nutritional support, given eady after injury, may help alleviate lung damage, reduce ventilatory support, hospital days and morbidity and mortality. Most notably, the demonstration of greatly improved cardiopulmonary function with an iNOS or PARP inhibitor should offer the opportunity for therapeutic intervention with a wide window of opportunity for instituting treatment.